Many current smokers show several risk factors that make smoking cessation more difficult. We propose to study the biological basis underlying how risk factors might lead to relapse to smoking. Some predictors of treatment failure for smoking cessation include weight concerns, heavy alcohol use, and female gender. This proposal will use animal models to determine how nicotine affects biological processes related to these risk factors, and will focus on how neuronal nicotinic acetylcholine receptors (nAChRs) can affect behavioral and biochemical responses related to these risk factors. These experiments will make use of pharmacological studies in normal rodents as well as experiments with mice lacking the beta2 subunit of the nAChR, transgenic lines with selective expression of these nAChRs in particular brain regions and knockout mice lacking the neuropeptides CART, galanin and NPY which have previously been generated. The aims of this project are: 1) to follow up on previous studies identifying second messenger pathways affected by nicotine treatment by using viral vector and local infusion strategies, identifying functional effects of these molecular changes on behaviors related to nicotine addiction; 2) to determine the relationship between nicotine, food intake, expression of hypothalamic peptides and appetitive behaviors in normal mice and rats undergoing behavioral paradigms following nicotine treatment, and in knockout mice lacking hypothalamic peptides related to feeding (the effect of naltrexone on these parameters will also be investigated); 3) to identify sex differences in these behavioral and neurochemical effects; 4) and to determine the concurrent and independent effects of chronic ethanol and nicotine treatment on biochemical and behavioral responses in appetitive behaviors. These experiments will contribute to the scientific background necessary for designing new strategies for treatment of smokers resistant to current cessation methods.